Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy

Although radiotherapy is a major and often effective modality in treating cancer patients, it can inflict serious damage on healthy tissues/organs. Because radiotherapy utilizes high energy radiation to kill cancer cells, injury to normal organ is almost inevitable. For example, the acute side effects of radiotherapy can occur on any surrounding normal tissues be it skin, brain or lung.

     Fortunately, many of the side effects caused by radiotherapy are reversible, but some may not become apparent until months or even years later, such as secondary tumor formation. Fortunately, modern technologies in radiotherapy can significantly reduce the radiation exposure of normal tissues and reduce the side effects thereof.

In general, the side effects of radiotherapy can be summarized in the following four categories:

          1. Damage to the DNA of normal cells
2. Damage to cell renewal
3. Activation of immunologic responses
4.  Other side effects of radiotherapy

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 1 - Introduction

PART II

Chapter 1

Introduction (cont'd)

Indeed, most of the therapeutic effect (DNA damage in the fast-growing cancer cells) by radiation is resulted from the DNA damage in cancer cells. Unfortunately, some normal cells can also be damaged by radiation because they are also fast-growing. These fast growing normal cells include bone marrow cells, hair follicle cells,  intestinal cells, and mucosal cells.

 Fortunately, there is a very important cellular function, DNA repair, by which a cell identifies and corrects damage to the DNA molecules. In fact, DNA repair process is constantly active as it responds to the continued damage in the DNA structure.

 Because cancer cells are not completely differentiated, their DNA repair capabilities tend to be less complete than those of normal cells. Therefore, cancer cells tend to be more susceptible to radiation damage as compared to normal cells. On the other hand, cancer cells can still rely on residual DNA repair capabilities to survive damage induced by radiotherapy or chemotherapy; this is one of the reasons cancer is not easy to treat.

In addition to radiation-induced DNA damage to normal cells, there are additional undesirable biological effects on the body, including immunological responses (such as abnormal levels of some cytokines including TNF-a, TGF-β, IL-12, and PGE2). These side effects will be discussed in the later section.

Indeed, the goal of radiotherapy is to damage as many cancer cells as possible, while limiting the damage to nearby healthy tissues/organs as much as possible. Nevertheless, it is almost impossible to have zero damage on normal cells. That is why the treatment plan is to focus the radiation to tumor cells. Let’s take a closer look at the side effects induced by radiotherapy in the following chapter.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 1 - Introduction

PART II

Chapter 1

Introduction (cont'd)

Radiotherapy has been used for both curative and adjuvant cancer treatment for many years. Adjuvant therapy refers to auxiliary/additional treatment for cancer; adjuvant radiotherapy is usually given after surgery or in conjunction with chemotherapy when a potential risk of relapse remains. Radiotherapy can also be given before surgery to reduce the mass of tumor to be removed.

Roughly speaking, 60% of all cancer patients receive radiotherapy, thus, radiotherapy might not be necessary for all cancer cases. For example, according to a scientific report in the New England Journal of Medicine, it was indicated that children with the most common form of leukemia can safely forego radiation therapy if they are treated with chemotherapy regimens tailored to their individual needs. The conclusion was based on a clinical trial involving 498 patients with acute lymphoblastic leukemia.  Nearly 94 percent of the patients were still alive 5 years after treatment, a result that compares favorably with other treatment studies.

An overly simplified schematic representation of how radiation works is shown in Fig. 2.1. Basically, radiation therapy works by damaging the DNA of cancer cells and hampering these cells from replicating. The damage to cancer cells is caused by radiation, which directly or indirectly breaks up the DNA chain. The indirect damage comes from free radicals including hydroxyl radical (HO^·), superoxide  (O₂^-), hydrogen peroxide (H₂O₂), peroxyl (ROO^·) and alkoxyl (RO^·) radicals, collectively called reactive oxygen species (ROS).  

Fig. 2.1   Schematic representation of how radiation works

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 1 - Introduction

PART II

Chapter 1

Introduction

Radiotherapy is also referred to as radiation therapy.  Radiotherapy deals with the treatment of cancer and it should not be confused with radiology, which deals with the study and application of radiation as a diagnostic tool.

Radiotherapy is a method of treating cancer patients by using ionizing radiation, which consists of either subatomic particles or electromagnetic waves that are energetic enough to knock off electrons from atoms or molecules to ionize them. Ionizing radiation comes from two sources shown below:

(1) Radiation is emitted by radioactive substances including cobalt, cesium, radium, uranium, radon, and plutonium;

(2) Radiation is produced by medical devices such as an x-ray machine.

Examples of ionizing particles include a particles, b particles (electrons), protons, and neutrons; examples of electromagnetic waves include x-ray, gamma ray, and ultraviolet (UV).

      Radiotherapy can be used to treat almost every type of solid tumor locally, including cancers of the breast, brain, lung, liver, cervix, pancreas, prostate, skin, stomach, and uterus. It can also be used to treat leukemia (cancer of blood-forming cells) and lymphoma (cancer of the lymphatic system, which is an important part of the immune system). In some cases, patients may receive a total body irradiation (TBI) for certain cancer, such as acute leukemia, as a pivotal part of bone marrow transplantation.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

D.7. Ototoxicity

Ototoxicity is the toxicity on the function of the ear. It can be caused by a number of chemotherapy agents and antibiotics. The symptoms of ototoxicity include hearing loss, balance disorder, and ringing noise. Some anticancer drugs, such as cisplatin, can cause damage of hearing or even hearing loss.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

D.6. Acral erythema

Acral erythema is a side effect of chemotherapy that can occur days to months after a patient begins treatment. Its symptoms include reddening, swelling, and desquamation of the skin, often of the palms and soles. Acral erythema has been reported in patients with prolonged treatment of cytotoxic anticancer drugs. Usually its symptoms can disappear within weeks after discontinuation of the offending drug.

 
© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

D.4. Mucositis

Mucositis refers to the inflammation on the mucous membrane in the digestive system. It is one of the side effects resulted from both chemotherapy and radiotherapy. It can occur anywhere along the gastrointestinal tract starting from the mouth. Mucositis in the mouth is often referred to as oral mucositis, which is a common side effect for patients treated by chemotherapy or radiotherapy. Severe mucositis can lead to other complications including infections and difficulty to eat.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

D.3. Cardiovascular toxicity (Cardiotoxicity)

Cardiotoxicity is associated with many anticancer drugs, particularly a very important class of anticancer drugs, anthracyclines. In fact, their use in cancer treatment is limited by a cumulative dose-dependent cardiotoxicity. Studies indicated that, at a cumulative dose of 550 mg/m², there was a significant increase in the development of heart failure; the use of smaller divided doses did decrease the chance of left ventricular ejection fraction. This cardiotoxicity induced by anthracyclines can cause irreversible heart failure and even fatality in some cases. 

In addition to anthracyclines, many other anticancer drugs may affect the cardiovascular system. In today’s oncology, combination therapy is becoming more popular and this could also increase the chance of cardiotoxicity.  

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

D. 2. Kidney damage (nephrotoxicity)

Kidneys play an essential role in the urinary system. In addition, kidneys have other functions, which include the regulation of electrolytes, blood pressure, acid-base balance, re-absorption of glucose & amino acids, and the production of erythropoietin (a hormone that stimulates stem cells in the bone marrow to produce RBCs).

Kidneys filter out creatinine (a break-down product of phosphocreatine in muscle) from blood so that there is little re-absorption of creatinine. Therefore, higher blood levels of creatinine indicate kidney may be injured and has a problem filtering out creatinine. If the filtering function of the kidney is deficient, it usually indicates that significant damage has occurred to normal nephrons (the basic structural and functional unit of the kidney) and blood levels of creatinine will rise. Therefore, creatinine levels in blood and urine may be used to calculate the creatinine clearance as one measurement of renal function.

A more complete kidney function measurement also includes blood urea nitrogen (BUN). Urea is a substance secreted by the liver, and removed from the blood by the kidney. A greatly elevated BUN (>60 mg/dL) generally indicates a moderate-to-severe degree of renal failure.

Unlike conventional drugs, cisplatin is not really “detoxified” by the liver, thus not only can it damage liver, it can also reach the kidney in the same molecular structure and still not easily excreted by the kidneys. As a result, bold levels of creatinine and BUN are usually elevated by cisplatin treatment. 

Nephrotoxicity is the major side effect of cisplatin, which evolves slowly but predictably after initial and repeated exposure of cisplatin. Nephrotoxicity induced by cisplatin may be related to reactive oxygen species (ROS).

In addition, among the earliest reactions of the kidney is the activation of the mitogen-activated protein kinase (MAPK) cascade which is typical of the stress response. The inflammatory cascade is an important determinant of the degree of renal failure induced by cisplatin.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

D.1. Liver damage

Liver is a vital organ and has a wide range of functions. Liver produces bile to aid in digestion through the emulsification of lipids and plays a major role in metabolism. Other functions of liver include hormone production, decomposition of red blood cells (RBCs), plasma protein synthesis, and detoxification of small and complex molecules.

Theoretically, all drugs are associated with certain toxicity (but to different extents) and liver is the major organ that is supposed to “detoxify” the drugs mainly by breaking down the drugs into metabolite(s). The other way for liver to make a drug less toxic is to make it more water soluble, thus more easily excreted out of the body and reduce potential toxicity. However, a small percentage of drugs are able to evade the “protection mechanism” by the liver. In this case, the drugs pass through the body’s major detoxifying guard (liver), damage liver, and move to other organs to exert other side effects.

A typical example of anticancer drugs with potential liver toxicity is cisplatin. Tyrosine kinase inhibitors are also associated with potential liver toxicity. Recently, the FDA required a “black box warnings” to be included on labels of several anticancer drugs to indicate the increased risk of liver injury including some tyrosine kinase inhibitors.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

D. Other Side Effects

The above side effects are directly related to the rapid growth of cells. There are other significant side effects that are not directly related to the fast growing of normal cells. These side effects include liver damage, kidney damage, pain, rash, constipation, nausea, vomiting, weight loss, ototoxicity, electrolyte abnormality, cardiotoxicity, and depression of the immune system. Among them, liver and kidney damages are most critical and are often the sources of other side effects. Some of these side effects are described below.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

C. Intestine (also see mucositis)

Chemotherapy often causes diarrhea. Crypt epithelial cells on the lining of the small intestine reproduce almost as fast as the bone marrow cells. Therefore, crypt cells are often easily damaged by chemotherapy.

Epithelial cells derived from crypt cells actively secrete electrolytes and play an important role in the re-absorption of water secretion in the intestines. During a normal digestive process, suitable amount of water are secreted into the lumen of the small intestine as part of the digestion process; most of the water is reabsorbed afterwards. Damage of crypt cells by chemotherapy disturbs the normal water-absorption process in the intestine, thus causing diarrhea.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

B. Hair

One of the most noticeable side effects of chemotherapy is hair loss. Remember that chemotherapy damages not only the fast-growing cancer cells but also the fast-growing normal cells? Because cells in the hair follicles are fast growing, they are more easily attacked by many cancer drugs, thus causing hair loss.

Hair loss caused by chemotherapy is often referred to as alopecia. Chemotherapy-induced alopecia is a significant problem in clinical oncology. Fortunately, the hair loss is usually not permanent and often the hair will begin to grow back several months after chemotherapy ends.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 3 - Side Effects of Chemotherapy

Part I

Chapter 3

Side Effects of Chemotherapy

      Chemotherapy can result in a wide range of side effects; many of them are due to its adverse activity on the fast-growing normal cells of the body such as bone marrow cells, hair follicle cells, and crypt epithelial cells on the small intestine lining. Other effects are due to its adverse activities on vital organs such as liver, kidney, and heart. Although the side effects induced by individual drugs can be different from drug to drug, they can be generalized and described below.

A.    Bone Marrow

Because most anticancer drugs tend to damage fast-growing bone marrow cells, which produce new blood cells, blood-related side effects are not unexpected as a result of chemotherapy. Basically, there are three major blood-related side effects resulted from bone marrow damage by chemotherapy; they are briefly described below:

A.1. Neutropenia

Neutropenia is defined as an abnormal decrease in the number of neutrophils, an abundant type of granular WBC that is highly destructive of microorganisms. A low WBC count may leave a patient vulnerable to bacterial infection and the chemotherapy regimen has to be put on hold until the WBC count is back to an acceptable level for the chemotherapy to resume. This is often a problem that interferes with the chemotherapy regimen.

A.2. Anemia

Anemia is defined as a deficiency of hemoglobin (Hb), which is an iron-containing protein that carries oxygen from the lungs to the body’s brains, muscles, tissues, and other organs; oxygen is critical to the health of tissues and organs. Symptoms of anemia include light headedness, tiredness, or dizziness when a patient stands up suddenly from a crouching position.

A.3. Thrombocytopenia

Thrombocytopenia refers to the condition of lower than normal platelet count. Platelets play a fundamental role in hemostasis (a complex process that causes the blood to clot and bleeding to stop) and are a natural source of growth factors including platelet-derived growth factor (PDGF), which plays a significant role in the repair and regeneration of connective tissues. A low platelet count may cause a person to experience bruising more easily or excessive bleeding. Patients with acute myeloid or lymphocytic leukemia often experience low platelet count. This is especially true when patients with acute leukemia are treated with chemotherapy

All of these three side effects are related to bone marrow damage and they can be diagnosed through the complete blood count (CBC) which represents the three types of cells in blood.

Currently, there are several drugs approved by the FDA to reduce individual side effects resulted from bone marrow damage. These drugs will be discussed later. In addition, some natural products have been claimed to have certain protective effects on bone marrow damage. However, one needs to look into the scientific evidence before making any conclusion or decision.

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.